Abstract/Summary Core D: Genetic Modification Core. Diabetes research is commonly conducted by comparing various functions in model organisms, including mice, following the introduction of specific alterations into the genome. The DRC Genetic Modification Core leverages a number of institutional facilities to provide a cost-effective, shared resource for the facile genetic modification of cells and animals needed for DRC investigators to complete studies relevant to type 1 and type 2 diabetes. Purpose: The Genetic Modification Core offers services that enable DRC researchers to: 1. generate complex targeting vectors for conventional knock-ins/knock-outs, genome-editing tools such as TALEN and CRISPR/Cas9, and standard lentiviral-mediated gene transfers. 2. modify ES or other cells with such vectors. 3. characterize and expand genetically modified cell lines. 4. deliver modified ES cells to blastocysts and generate modified mice lines. 5. inject fertilized eggs with TALEN and CRISPR/Cas9 for direct in vivo genome editing. 5. use transgenic methods to create genetically modified mice. 6. assist investigators with the optimal storage of, recovery of, and transfer of modified mouse lines. Benefits to DRC Community: The Genetic Modification Core enables access of DRC researchers to technologies and expertise that would require years to replicate within individual laboratories. In the past 2 years, the facilities that comprise the DRC Genetic Modification Core assisted 77 investigators from 35 DRC laboratories with an average of 269 procedures annually. 61 different currently active projects totaling $15,903,865 annual direct costs ($10,694,539 from NIH sources) have benefited through these efforts. The DRC Genetic Modification Core coordinates multiple UCSF facilities that provide these technically challenging services to DRC researchers. The DRC Core lowers barriers to enable the use of these necessary capabilities by DRC researchers. The DRC Core also provides feedback and resources to the component facilities so that they evolve to meet the emerging genetic modification needs of DRC researchers. Technology Development: All DRC Cores interact with DRC members to define service needs to be developed by Core Staff. The DRC Executive Committee selects proposals that meet emerging needs by DRC members. Within the past funding period, DRC support has developed the Core's ability to generate both knock-ins and transgenics in non-obese diabetes (NOD) mouse background, lentivirus-based methods for transgenesis, and TALEN and CRISPR/Cas9-directed modifications in a variety of model organisms including mice, flies and worms. This support for the development of new technologies within the Core thus ensures that DRC investigators have cost-effective access to the most up-to-date genetic modification tools they require.